Methods of treating traumatic brain injury by vagus nerve stimulation

ABSTRACT

Methods of modulating brain neural plasticity, improving memory and learning, improving recovery from traumatic brain injury, preventing epilepsy, treating memory disorders and chronic memory impairment, and treating persistent impairment of consciousness in humans and animals by vagus nerve stimulation are provided. These methods comprise selecting an appropriate human or animal subject and applying to the subject&#39;s vagus nerve an electrical stimulation signal having parameter values effective in modulating the electrical activity of the vagus nerve in a manner so as to modulate the activity of preselected portions of the brain.

This application claims the benefit of priority of U.S. ProvisonalApplication Ser. No. 60/018,813, filed May 31, 1996, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to methods and apparatus for modulatingneural plasticity in the nervous system. Neural plasticity includesphenomena such as memory and learning consolidation processes, as wellas recovery of function following traumatic brain injury. The methods ofthe present invention are directed to modulating neural plasticity,improving memory and learning consolidation processes, cognitiveprocessing, and motor and perceptual skills in both normal subjects andsubjects suffering from chronic memory impairment, alleviating symptomsand improving outcome in subjects suffering from traumatic brain injury,preventing the development of epilepsy in subjects prone to developingthis condition, and treating persistent impairment of consciousness.These methods employ electrical stimulation of the vagus nerve in humanor animal subjects via application of modulating electrical signals tothe vagus nerve by use of a neurostimulating device.

2. Description of Related Art

Vagal Afferents and their Influence on Physioloay and Behavior

The vagus nerve comprises both somatic and visceral afferents (inwardconducting nerve fibers that convey impulses toward a nerve center suchas the brain or spinal cord) and efferents (outward conducting nervefibers that convey impulses to an effector to stimulate the same andproduce activity). The vast majority of vagal nerve fibers are C fibers,and a majority are visceral afferents having cell bodies lying in massesor ganglia in the neck. For the most part, the central projectionsterminate in the nucleus of the solitary tract, which sends fibers tovarious regions of the brain such as the hypothalamus, thalamus, andamygdala. Other projections continue to the medial reticular formationof the medulla, the cerebellum, the nucleus cuneatus, and other regions.The solitary nucleus has important pathways to brain regulatorynetworks, including the serotonergic nuclei and the noradrenergicnuclei. These neurotransmitter systems are crucial for memory, learning,cognitive and sensory/perceptual processing, and motor skills. Theseneurotransmitters also prevent the development of epilepsy, i.e., theyare antiepileptogenic, and are important for the processes that subservebrain recovery following traumatic injury.

The majority of vagus nerve fibers are viscerosensory afferentsoriginating from receptors located in the lungs, aorta, heart, andgastrointestinal tract, and convey, among other things, cardiopulmonaryand nocicepive information to various forebrain and brainstem structures(Cechetto, D. F. (1987) Federation Proceedings 46:17-23). Threepopulations of vasal afferents are known to exist: the vastly abundantunmyelinated C fibers involved in pain mediation, and small myelinated Bfibers and large A fibers which subserve autonomic reflexes and probablymore complex visceroendocrine responses, such as glucose metabolism andfluid homeostasis (Barraco, I.R.A. (1994) Nucleus of the Solitary Tract,CRC Press, Boca Raton). Nearly all vagal afferents terminate in thenucleus of the solitary tract (NTS), where the information they carry isfirst integrated before being divergently projected to each rostrallevel of the neuroaxis. Because NTS neurons impinge on a number of CNSstructures and regions, including the hypothalamus, hippocampus,amygdaloid complex, dorsal raphe nucleus, and mesencephalic reticularformation (Rutecki, P. (1990). Epilepsia 31 (Suppl. 2):51-56), anequally large number of cognitive, somatic, and visceral operations canbe initiated or coordinated with autonomic information. Thus, as onemight expect, neural signals sent via vagal afferents have a profoundimpact on CNS function that, in turn, influence general behaviors andarousal. For instance, electrical stimulation of the cervical vagus canmodify the electrophysiological profile of neocortical, thalamic, andcerebellar neurons. These and other changes in supramedullary circuitsare thought to precipitate overt changes in, for example, sleep, feedingbehavior, responsiveness to noxious stimuli, and monosynaptic muscularreflexes (Rutecki, supra).

Vagus Nerve Stimulation and the Brain

Vagus nerve stimulation has been shown to cause activation of severalparts of the brain that are specifically involved in cognitiveprocessing, memory, learning, sensory and motor processing, and affectsregions of the brain that are prone to developing epilepsy or whichregulate the development of epilepsy (Naritoku et al. (1995) In Ashleyet al., Eds., Traumatic Brain Injury Rehabilitation, CRC Press, BocaRaton, pp. 43-65). These studies demonstrate that vagus nervestimulation activates the amygdala and cingulate cortex, which areinvolved in learning and cognitive processing. Such stimulation alsoactivates several thalamic nuclei which serve relay functions. Inaddition, it activates several sensory nuclei, including the auditory,visual, and somatic sensory systems. Finally, vagus nerve stimulationactivates monoaminergic nuclei, especially the locus ceruleus and A5groups, which provide norepinephrine to the brain. Monoamines arecrucial for both learning and memory, and for preventing the developmentof epilepsy (Jobe et al. (1981) Biochem. Pharmacol. 30:3137-3144).

Modulation of Memory by Arousal

Both anecdotal and scientific reports have long suggested that somememories are remembered far more distinctly than others when thosememories were stored at the time of a significant emotional or stressfullife event. This appears to be an important memory mechanism by whichthe brain selectively enhances the storage and retrievability of moreimportant memories, while minimizing interference from those that arecomparatively inconsequential. The research to date indicates that thestorage of permanent memories is susceptible to enhancing or disruptinginfluences shortly after an initial exposure to salient information(McGaugh, J. L. (1989) Annual Review of Neuroscience 12:255-287;McGaugh, J. L. (1990) Psychological Science 1:15-25; Squire, L. R.(1987) Memory and Brain, Oxford University Press, New York). In clinicaland animal studies, improved retention can be produced by a wide varietyof treatments, including the peripheral administration of certainhormones, neuromodulators, and stimulant drugs, such as amphetamine. Onefactor which seems to be common to those agents that enhance memory isthat most are related in some way to arousal.

Arousal is associated with the release of adrenal catecholamines andnumerous other substances such as the pituitary hormones ACTH andvasopressin. Peripheral administration of these substances hasconsistently been shown to modulate memory in a dose- and time-dependentfashion (McGaugh et al. (1989) "Hormonal Modulation of Memory" In Brushet al., Eds., Psychoendocrinology, Academic Press, New York). Forinstance, when moderate doses of epinephrine or its agonists are givenshortly after training on a memory task, there is enhancement ofretention performance measured some time later (Gold et al. (1977)Behavioral Biology 20:197-207). Importantly, many substances thatmodulate memory when either endogenously released or deliveredsystemically do not freely cross the blood-brain barrier, and aretherefore unlikely to influence memory by direct pharmacological actionon the brain. Instead, they appear to activate peripheral receptors thatin turn send neural messages to those central nervous system (CNS)structures involved in memory consolidation.

Role of the Vagus Nerve in Mediating Arousal-induced Memory Modulation

The vagus nerve appears to be at least partially responsible for theobserved memory-modulating effects of peripherally-acting agents.Williams et al. ((1991) "Vagal afferents: A possible mechanism for themodulation of memory by peripherally acting agents" In: Frederickson etal., Eds., Neuronal control of bodily function, basic and clinicalaspects: Vol. 6., Peripheral signaling of the brain: Role inneuralimmune interactions, learning and memory, Hogrefe and Huber,Toronto, pp. 467-472) and Williams et al. ((1993) Physiology andBehavior 54:659-663) demonstrated that severing the vagus nerve belowthe level of the diaphragm attenuated the memory-enhancing effects of4-OH amphetamine, an amphetamine derivative that does not freely enterthe CNS, as well as the memory-impairing effects ofperipherally-administered Leu-enkephalin. Similar attenuation has alsobeen demonstrated with respect to the memory-modulating capacity ofcholecystokinin (Flood et al. (1987) Science 234:832-834).

Clinical Measurements of Memory Modulation Induced by Arousal

Arousal has also been demonstrated to affect memory performance inhumans. Nielson et al. ((1996) Neurobiology of Learning and Memory66:133-142) studied the effects of muscle-tension-induced arousal onmemory storage and later retention performance. In that study, amoderate level of muscle-tension-induced arousal was produced by havingsubjects, young college students, squeeze a hand dynamometer at varioustimes during or following presentation of one practice and four 20-itemword lists presented as slides (one every 5 sec.). Thus, each subjectparticipated in four arousal conditions: no muscle tension; muscletension (100 sec.) during learning of the list (encoding); muscletension during the 100-sec. memory consolidation interval (storage); andmuscle tension (100 sec.) during the immediate recall of the words(retrieval). List order remained the same for all subjects, but theorder of arousal conditions was counterbalanced. A final recognitiontest was given 5 min. after completion of all lists. The resultsdemonstrated that muscle-tension-induced arousal during the memoryconsolidation interval significantly enhanced final recognitionperformance.

In another phase of this investigation, subjects were given a series oftwo practice and twelve 200-word paragraphs to read. Half of the testparagraphs contained highlighted words. Immediately following completionof each paragraph, two questions (one factual and onelogical-inferential) were asked about the content of that paragraph. Inaddition, for the paragraphs containing highlighted words, subjects wereasked to recall as many of the highlighted words as they could. For themuscle-tension arousal paragraphs, immediately after the paragraph wascompleted, the subject was handed the hand dynamometer and asked tosqueeze it during the answering of the questions and the recalling ofhighlighted words. Following completion of the final paragraph and allquestions, a final recognition test of all highlighted words was given.The results indicated significant enhancement of retention performancefor the muscle-tension arousal paragraphs compared to the no-tensionparagraphs, indicating that arousal can enhance memory storage in aworking-memory task.

This experiment was replicated using elderly subjects (Nielson et al.(1994) Behavioral and Neural Biology 62:190-200). In this experiment,there were 22 normotensive elderly subjects, 21 elderly subjects takingeither calcium-channel blockers or angiotensin-converting enzymeinhibitors to control hypertension, and 21 elderly subjects takingbeta-blocker antihypertensive medications. The normotensive elderlysubjects and those taking non-beta-blocker medications all showedenhanced long-term memory performance as a result ofmuscle-tension-induced arousal. However, those subjects chronicallytaking beta-receptor-antagonist medications showed no enhancement ofretention performance. These findings suggest that when arousal occurs,there is an enhanced release of adrenal catecholamines (epinephrine andnorepinephrine), and that these substances activate peripheral receptorsthat send neural messages to the brain to modulate memory storageprocesses. When these receptors are antagonized by beta-blocker-typeantihypertensive medications, the normal processes of memory modulationare impaired. Since epinephrine and norepinephrine do not freely crossthe blood-brain barrier, their release by arousal likely modulatesmemory by causing the transmission of neural messages to the brain,possibly via the vagus nerve pathway. Therefore, antagonizing peripheralbeta receptors by beta-blocker-type antihypertensive medicationsprevented the initiation of these messages by the receptors, thuseffectively attenuating the normally occurring modulation of memorystorage processes by arousal.

Possible Role of Specific Central Serotonergic and NoradrenergicPathways in the Modulation of Memory by Vaqus Nerve Stimulation

The dorsal raphe nucleus is one of two monoaminergic brainstem nuclei,the other being the locus coeruleus, that receives indirect input fromvagal afferents. Both nuclei then project that information to variousother brain structures implicated in learning and memory processes, suchas the amygdaloid complex, hippocampus, and mesencephalic reticularformation (Vertes et al. (1994) Journal of Comparative Neurology340:11-26). Thus, the dorsal raphe nucleus and locus coeruleus are wellsuited to regulate the memory-modulating effects of autonomic arousal.In addition, the dorsal raphe nucleus interacts with the amygdaloidcomplex to produce conditioned fear responses to inescapable shock andin learned-helplessness paradigms (Maier et al. (1993) BehavioralNeuroscience 107:377-788). Elevations in the release of serotonin by thedorsal raphe nucleus also reportedly increase anxiety (Iversen (1984)Neuropharmacology 23:1553-1560). It is therefore possible that changesin autonomic activity and arousal are reflected in alterations of dorsalraphe nucleus activity and the subsequent release of serotonin ontoneurons found in the amygdaloid complex. It is therefore possible thatchanges in autonomic activity and arousal are transmitted to the brainvia the vagus nerve and are reflected in alterations in the activity ofneurons in the dorsal raphe nucleus and the subsequent release ofserotonin onto neurons of the amygdaloid complex, a brain structurewell-known to be involved in the modulation of learning and memory.

Noradrenergic systems are also known to modulate memory consolidationand amygdaloid complex activity (cf. McGaugh (1989) Annual Review ofNeuroscience 12:255-287); however, Holdefer et al. ((1987) BrainResearch 417:108-117) demonstrated that locus coeruleus-maintaineddischarge does not correlate with the memory modulation produced byperipherally-injected 4-OH amphetamine, D-amphetamine, or epinephrine.Although the locus coeruleus receives indirect vagal input, it alsoreceives serotonergic projections from the dorsal raphe nucleus.Consequently, dorsal raphe nucleus activity might suppress theresponsiveness of locus coeruleus neurons to autonomic stimulation,thereby increasing serotonergic control over the amygdaloid complex andother brain areas during the memory consolidation period. Thishypothesis is supported directly by studies of Naritoku et al.((1995) InAshley et al., Eds., Traumatic Brain Injury Rehabilitation, CRC Press,Boca Raton, pp. 43-65), which demonstrated activation of the locusceruleus and A5 nuclei, which are noradrenergic neurons. Preliminaryevidence of Krahl et al. ((1994) Society for Neuroscience Abstracts20:1453) also indicates that cells found in the dorsal locus coeruleusrespond differentially to those found in either the ventral locuscoeruleus or subcoeruleus following vagus nerve stimulation.

Modulation of Memory by Peripherally-Acting Substances

Previous research has suggested that the vagus nerve plays a role in themodulation of learning and memory brought about by peripherally-actingsubstances such as catecholamines, peptides, etc. (Williams et al.(1991) In Frederickson et al., Eds., Neuronal Control of BodilyFunction, Basic and Clinical Aspects: Volume 6, Peripheral Signaling ofthe Brain: Role in Neural-Immune Interactions, Learning and Memory,Hogrefe & Huber, Toronto, pp. 467-472; Williams et al. (1993) Physiologyand Behavior 54:659-663; Flood et al. (1987) Science 234:832-834). Thiswork suggests that the vagus nerve may represent a neural pathwaythrough which such substances alter retention performance. However, theeffects of direct electrical activation of the vagus nerve on learningand memory in humans have not been previously studied.

Chemical vs. Direct Electrical Stimulation of the Vagus Nerve ChemicalStimulation

Hormonal or chemical (drug) agents function by interacting with specificreceptor proteins on neurons. When activated by a neurotransmitter,hormone, or drug, these receptor proteins then either: 1) cause achemical change in the cell, which indirectly causes ion channelsembedded in the membrane to either open or close, thus causing a changein the electrical potential of the cell, or 2) directly cause theopening of ion channels, which causes a change in the electricalpotential of the cell. This change in electrical potential then triggerselectrical events that are conducted to the brain by the axons ofsensory nerves such as those contained in the vagus.

Neural activity is constantly being controlled by the endogenous releaseof hormones, neurotransmitters, and neuromodulators. However, fortherapeutic or experimental purposes, changes in neural activity canalso be produced by the administration of chemical or hormonal agents(drugs). When administered exogenously, these agents interact withspecific proteins either inside neurons or on the surface of the cellmembrane to alter cell function. Chemical agents can stimulate therelease of a neurotransmitter or family of neurotransmitters, block therelease of neurotransmitters, block enzymatic breakdown ofneurotransmitters, block reuptake of neurotransmitters, or produce anyof a wide variety of other effects that alter nervous systemfunctioning. A chemical agent can act directly to alter central nervoussystem functioning or it can act indirectly so that the effects of thedrug are carried by neural messages to the brain. A number ofchemical/hormonal agents such as epinephrine, amphetamine, ACTH,vasopressin, pentylene tetrazol, and hormone analogs all have been shownto modulate memory. Some act by directly stimulating brain structures.Others stimulate specific peripheral receptors.

Electrical Stimulation

In contrast, electrical stimulation of a nerve involves the directdepolarization of axons. When electrical current passes through anelectrode placed in close proximity to a nerve, the axons aredepolarized, and electrical signals travel along the nerve fibers. Theintensity of stimulation will determine what portion of the axons areactivated. A low-intensity stimulation will activate those axons thatare most sensitive, i.e., those having the lowest threshold for thegeneration of action potentials. A more intense stimulus will activate agreater percentage of the axons.

Electrical stimulation of neural tissue involves the placement ofelectrodes inside or near nerve pathways or central nervous systemstructures. Functional nerve stimulation is a term often used todescribe the application of electrical stimulation to nerve pathways inthe peripheral nervous system. The term neural prostheses describesapplications of nerve stimulation in which the electrical stimulation isused to replace or augment neural functions which have been damaged insome way. One of the earliest and most successful applications ofelectrical stimulation was the development of the cardiac pacemaker.More recent applications include the electrical stimulation of theauditory nerve to produce synthetic hearing in deaf patients, and theenhancement of breathing in patients with high-level spinal cord injuryby stimulation of the phrenic nerve to produce contractions of diaphragmmuscles. Recently, electrical stimulation of the vagus nerve is beingused to attenuate epileptic seizures.

The basis of the effects of electrical stimulation of neural tissuecomes from the observation that action potentials can be propagated byapplying a rapidly changing electric field near excitable tissue such asnerve or muscle tissue. In this case, the electrical stimulation, whenpassed through an electrode placed in close proximity to a nerve,artificially depolarizes the cell membrane which contains ion channelscapable of producing action potentials. Normally, such action potentialsare initiated by the depolarization of a postsynaptic membrane. However,in the case of electrical stimulation, the action potentials arepropagated from the point of stimulation along the axon to the intendedtarget cells (orthodromic conduction). However, action potentials alsotravel from the point of nerve stimulation in the opposite direction aswell (antidromic conduction).

Gold and his co-workers have demonstrated that administration of glucoseto rats or humans following a learning experience enhances laterretention performance (Gold, P.E. (1986) Behavioral and Neural Biology45:342-349; Manning et al. (1993) Neurobiology of Aging 14:523-528).Gold has suggested that vagus nerve stimulation may activate descendingefferent vagus pathways which directly and indirectly stimulate theliver to release glucose into the systemic circulation. This increasedplasma glucose has been postulated to serve as a second messenger tomodulate the storage of memories. However, the present investigatorsrecently demonstrated in rats that blocking descending vagus nervepathways by a topical application of the local anesthetic lidocaine tothe nerve did not attenuate memory enhancement produced by vagus nervestimulation (Clark, K. B., Smith, D. C., Hassert, D. L., Browning, R.B., Naritoku, D. K., and Jensen, R. A. (submitted for publication)).Posttraining electrical stimulation of vagal afferents with concomitantefferent inactivation enhances memory storage processes in the rat(Society for Neuroscience Abstracts, 22). These results clearly indicatethat the ascending neural messages resulting from vagus nervestimulation are the active agent mediating the observed enhancement inmemory storage processes.

Few experiments in contemporary neuroscience research employ directnerve tract stimulation to alter global aspects of behavior such as thestorage of memories. Most researchers attempt to alter memory and/orbehavior by either administering a drug that activates specific neuralsystems or by electrically stimulating specific groups of neurons in thecentral nervous system. Thus, the present inventors' discovery of vagusnerve stimulated enhancement of particular neural processes as disclosedherein is novel. In this case, stimulation of the vagus nerve results inthe activation of a variety of processes in the brain that result inchanges in brain function. It is likely that only some of theseprocesses are related to the modulation of memory storage and that thisstimulation also modulates other changes or plastic processes in thebrain as well. That direct vagus nerve stimulation influences plasticprocesses related to brain development or the recovery of function frombrain injury is a very good possibility given the already demonstratedeffect on one major form of neural plasticity, i.e., memory storage.

Modulation of Memory in Rats by Electrical Stimulation of Vagus Nerve

Jensen and co-workers (Clark, K. B., Krahl, S. E., Smith, D. C., andJensen, R. A. (1994) Society for Neuroscience Abstracts 20: 802; Clark,K. B., Krahl, S. E., Smith, D. C., and Jensen, R. A. Neurobiology ofLearning and Memory 63:213-216) demonstrated that direct electricalstimulation of the vagus nerve at a particular intensity (0.4 mA) andfrequency (20 Hz) administered shortly after a learning experienceresulted in a pattern of effects on retention performance similar tothat reported following the administration of some drugs that do notfreely cross the blood-brain barrier (chemical stimulation of peripheralreceptors). In this experiment, vagus nerve stimulation (0.4 mA) givenduring the memory consolidation interval modulated later retentionperformance such that stimulated rats showed better memory. Stimulationat either a lower (0. 2 mA) or higher (0.8 mA) intensity had no effecton retention.

Whether one could reasonably predict that this effect observed in ratsmight extrapolate to human beings is doubtful in view of the substantialdifferences in neuroanatomy and complexity of memory processes betweenlaboratory rodents and humans. The experiments performed in rats werebased on a single-trial training task of great simplicity, i.e., aninhibitory avoidance task. In this task, the animals were placed in arunway, one end of which was brightly illuminated, while the other endwas darkened. As rats are nocturnal, burrowing animals, they typicallymove quickly from the lighted end into the darkened end when the doorseparating the two ends of the runway is opened. A mild electricalfootshock was delivered in the darkened end. Immediately thereafter,each animal was removed from the runway and returned to its home cage,where it received either no stimulation or vagal stimulation throughchronically implanted cuff electrodes on the left cervical vagus nerve.Retention was tested 24 hours later. Latency to step through into thedarkened end was taken as the measure of retention.

In the case of human memory, especially verbal memory, the neuralsystems involved are much more complex than those involved in thelearning of a simple avoidance training task by the rat. Learning ofconcepts, vocabulary, and procedures by humans is qualitatively andquantitatively different from a rat's learning to avoid the end of arunway where punishment, i.e., a footshock, has occurred. Many humanbrain structures, such as those that mediate language, for example, donot even exist in the laboratory rat. It is therefore possible that theforegoing phenomenon observed in rats is limited to infrahumans, and itis therefore not reasonably predictable that vagal nerve stimulationmodulation of memory in the laboratory rat would generalize to humansubjects. The applicability of vagal nerve-stimulated modulation oflearning of tasks such as complex verbal tasks has for the first timebeen demonstrated by the present inventors as disclosed herein.

Uniqueness of Vagus Nerve Stimulation in Modulating Memory

Vagus nerve stimulation is completely unlike other experimentalmanipulations known to modulate memory. Drugs, hormones, and electricalbrain stimulation are all known to alter memory storage processes. Forexample, administration of adrenal hormones (such as epinephrine) orpituitary hormones (such as ACTH) after a learning experience results inthe enhancement of memory in a dose-dependent manner. Very low doses arewithout effect; intermediate doses tend to improve retentionperformance; very high doses tend to cause amnesia. These hormonalsubstances and pharmacological agents are thought to act on memoryprocesses by activating specific receptors in the periphery which, inturn, send neural messages to the brain to either enhance or impair thestorage of memories.

In contrast, vagus nerve stimulation directly activates one principalnerve pathway connecting the central nervous system with peripheralstructures located in the viscera. In this case, the step of chemicallyactivating receptors in the periphery is avoided. Rather, actionpotential messages in the nerve are directly triggered by the electricalstimulation. These messages pass along the vagus nerve and activatethose brain structures in which the nerve fibers terminate. The resultis release of neurotransmitters and activation of still other brainstructures. Following this, there are alterations in brain function suchas the well-established reduction in epileptic seizures and the recentlydemonstrated enhancement in CNS plasticity, specifically, facilitationof memory storage processes.

Brain Neural Plasticity

The term "neural plasticity" can be viewed as encompassing thosestructural alterations in the brain that lead to changes in neuralfunction. Such changes in neural function then lead to changes inbehavior or in the capacity for behavior. Learning and memory can bethought of as one common form of neural plasticity. The storage ofmemories following a learning experience is the result of structural andfunctional changes that occur in specific groups of neurons. Every timesomething is learned, there is a change in that organism's nervoussystem which encodes that new information. Such a change does notnecessarily result in an immediate change in behavior; rather, itresults in an alteration in behavior potential.

During development of the nervous system both before and after birth,there are profound plastic changes taking place which shape thestructure and function of the brain. Before birth, groups of nerve cellsform, migrate to their assigned location in the brain, and then makeconnections with other cells. Following birth, neurons continue tosprout new projections, and these branches expand dramatically incomplexity, sometimes extending great distances, and making connectionswith other cells of the nervous system. This process, another form ofneural plasticity, continues at a decreasing rate from the time of birthuntil adolescence.

Neural plasticity is thought to be moderated by a wide variety ofcellular and molecular events, including transcription and translationof DNA, which produces cellular proteins that cause long-term changes inneuronal function. One such signal is thought to be the protein fos,which is produced by neurons under conditions of high activity. Thisprotein signals the transcription of other proteins, and is thought tomediate long-term neuronal changes. It may be induced by severalneurotransmitters, including excitatory amino acids and monoamines.Naritoku et al. ((1995) Epilepsy Research 22:53-62) demonstrated thatfos is induced by stimulation of the vagus nerve in widespread areas ofthe brain (see FIG. 3), thus demonstrating that vagus nerve stimulationactivates many areas in the brain, and furthermore, appears to inducethe production of a protein that causes further transcriptional eventsthat may in turn mediate neural plasticity.

Memory and Learning, and their Modulation

It is clear that learning and memory are not unitary processes and thatthere are different types of memory that are mediated by different brainstructures. On one level of analysis, it is possible to distinguishbetween two broad classes of memories, "explicit" and "implicit." Whenexplicit memory is to be assessed, measures such as recall andrecognition are used. These measures depend on the consciousrecollection of previously stored information. Recognition performanceis generally considered to be among the most sensitive measures ofexplicit memory. Tests of implicit memory infer learning from theeffects that experience or practice has on the subject's performance.For example, prior exposure to words will enhance later performance inrecognizing these words when they are flashed very rapidly on a screenor presented as word fragments.

Another distinction between types of memory is that between "procedural"and "declarative" memories. These are typically defined as "knowing how"and "knowing that." Procedural memories include perceptual, cognitive,and motor skills, while declarative memory includes such things asfacts, events, and routes between places. Both forms of memory can bemodulated by various agents, although declarative memories are moresubject to disease-produced amnesia than are procedural memories.

We know from our own every-day experiences that some occurrences orevents are remembered clearly while others are remembered poorly orperhaps not at all. This is true of procedural and declarative memorieswhether assessed implicitly or explicitly. It is well established inlaboratory animals that retention can be either impaired or enhanced byexperimental treatments such as electrical brain stimulation, theadministration of stimulant drugs, or the administration of hormones(McGaugh et al. (1972) Memory Consolidation, San Francisco, AlbionPublishing Company). What is commonly reported is that retentionperformance, measured some time after the learning experience, can bemodulated by changing the parameters of training or by theadministration of chemical stimulation shortly after the time oftraining. Although the underlying mechanisms that mediate memorymodulation are not well understood, it appears that several commonprinciples may mediate differences in the quality of remembering.

One major variable influencing retention performance appears to be levelof arousal. Early in the development of the behavioral sciences, theYerkes-Dodson principle was described (Yerkes et al. (1908) Journal ofComparative Neurology and Psychology 18:459-482). This principle ischaracterized by an inverted U-shaped relationship between the amount ofmotivation or arousal and the resultant level of behavioral performance.This relationship can be seen between the level of arousal and theeffectiveness of memory storage processes. For example, either low orvery high levels of arousal produce relatively poor learning and memory.However, an intermediate level of arousal results in relatively goodmemory for a learning experience (McGaugh, J. L. (1973) Annual Review ofPharmacology 13:229-241). A similar curve showing an inverted U-shapedfunction is seen in the data obtained using laboratory rats and vagusnerve stimulation delivered after training. It is important to note thatmemory is modulated by post-training treatment. In such an experiment,the learning occurs in a normal state and then after training, thetreatment is administered. Thus, the primary effects of the treatmentare on the storage of the memory and not on other aspects of theexperience such as perception or level of motivation.

Traumatic Brain Injury

Another form of neural plasticity is recovery of function followingbrain injury. As in the case of memory formation or brain development,in this case too there is a change in the ways that neurons interactwith one another. When neurons are lost due to disease or trauma, theyare not replaced. Rather, the remaining neurons must adapt to whateverloss occurred by altering their function or functional relationshiprelative to other neurons. Following injury, neural tissue begins toproduce trophic repair factors, such as nerve growth factor and neuroncell adhesion molecules, which retard further degeneration and promotesynaptic maintenance and the development of new synaptic connections.However, as the lost cells are not replaced, existing cells must takeover some of the functions of the missing cells, i.e., they must "learn"to do something new. In part, recovery of function from brain traumaticdamage involves plastic changes that occur in brain structures otherthan those damaged. Indeed, in many cases, recovery from brain damagerepresents the taking over by healthy brain regions of the functions ofthe damaged area. Thus, such recovery can be viewed as the learning ofnew functions by uninjured brain areas to compensate for the loss offunction by other regions. Studies of the effect of vagus nervestimulation on fos production demonstrate that such stimulation inducestranscriptional events that produce proteins which in turn stimulatefurther cellular transcriptional activity (Hughes et al. (1995)Pharmacol. Rev. 47:133-178). Increases in neuronal cellular activitywill enhance the recovery of function after traumatic brain injury.

Traumatic brain injury results from a wide variety of causes including,for example, blows to the head from objects; penetrating injuries frommissiles, bullets, and shrapnel; falls; skull fractures with resultingpenetration by bone pieces; and sudden acceleration or decelerationinjuries.

Traumatic brain injury represents a growing medical problem in theUnited States and elsewhere. It is an extremely costly illness, not onlydue to the expenses arising from the acute care required, but also dueto the costs associated with rehabilitation and any resulting long-termdisability. A therapy that would accelerate the recovery process and/orimprove outcome would be highly beneficial to afflicted persons. As manyas 40% of persons with severe head injury proceed to develop epilepsy,which further impedes functional recovery from traumatic brain injury.In addition, epilepsy itself further limits function in this population.A therapy that prevents the genesis of epilepsy would thereforesignificantly benefit traumatically brain injured persons.

Memory Disorders

A third form neural plasticity relates to the treatment of chronicmemory disorders. These disorders arise from, for example, Alzheimer'sDisease, encephalitis, cerebral palsy, Wernicke-Korsakoff(alcohol-related) syndrome, brain injury, post-temporal lobectomy,Binswanger disease, Parkinson's disease, Pick's disease, stroke,multi-stroke dementia, multiple sclerosis, post arrest hypoxic injury,near drowning, etc.

SUMMARY OF THE INVENTION

As demonstrated in the non-limiting Examples disclosed infra, vagusnerve stimulation employed with the appropriate parameters can improvememory and learning in human and animal subjects. When delivered shortlyafter a learning experience, vagus nerve stimulation results in theinitiation of nerve impulses that travel to those brain structures wherethe nerve terminates, predominantly the nucleus of the solitary tract.The resultant release of neurotransmitters and activation of cells inthe vagus nerve target structures results in the activation of otherbrain areas including those such as the amygdala and hippocampus thatare known to be involved in memory storage and the modulation of memory.The result is facilitated memory storage (consolidation) and improvedretention performance when memory is measured at some later time. Vagusnerve stimulation can also be employed in the treatment of human andanimal subjects suffering from various forms of brain damage or fromtraumatic head injury.

It is well known that central nervous system neurons do not regeneratefollowing loss due to disease or injury. Therefore, in order for thereto be recovery of function, healthy areas of the brain must "learn" totake over the functions of the damaged area.

As discussed above, both phenomena are manifestations of brain neuralplasticity.

Accordingly, the present invention provides a number of methods ofinfluencing various aspects of brain neural plasticity, including:

A method of modulating brain neural plasticity in a human or animalsubject, comprising the steps of:

(a) applying to the vagus nerve of said human or animal subject astimulating electrical signal having parameters sufficient to cause aphysiological, structural, or neuronal connective alteration in thebrain;

(b) changing neural function in said brain as a consequence of saidalteration; and

(c) changing behavior, or the capacity for behavior, in said human oranimal subject.

A method of improving learning or memory in a human or animal subject,comprising:

(a) exposing or subjecting a human or animal subject to a learningexperience;

(b) applying to the vagus nerve of said human or animal subject astimulating electrical signal having parameters sufficient to enhancememory storage or consolidation processes; and

(c) improving storage of the memory of said learning experience, orimproving retention of said learning experience, in said human or animalsubject.

A method of treating a human or animal subject suffering from a symptomcaused by traumatic brain injury or characteristic of traumatic braininjury, comprising:

(a) selecting a human or animal subject suffering from a symptom causedby traumatic brain injury or characteristic of traumatic brain injury;

(b) applying to the vagus nerve of said human or animal subject astimulating electrical signal having parameters sufficient to alleviatesaid symptom;

(c) monitoring said human or animal subject via a member selected fromthe group consisting of clinical outcome, a clinical test, a laboratorytest, and combinations thereof, to determine if said symptom has beenalleviated, or if further stimulation of said vagus nerve is required;and

(d) if required, further stimulating said vagus nerve and monitoringsaid human or animal subject as in preceding steps (b) and (c),respectively, until said symptom has been alleviated.

A method of preventing the development of epilepsy in a human or animalsubject, comprising the steps of:

(a) selecting a human or animal subject predisposed to, or renderedsusceptible to, developing epilepsy;

(b) applying to the vagus nerve of said human or animal subject astimulating electrical signal having parameters sufficient to preventepilepsy in said subject;

(c) monitoring said subject to determine if further stimulation of saidvagus nerve is required to prevent epilepsy in said subject; and

(d) if required, further stimulating said vagus nerve and monitoringsaid subject as in preceding steps (b) and (c), respectively, to preventdevelopment of epilepsy in said subject.

A method of treating a human or animal subject suffering from a symptomselected from the group consisting of memory impairment, a learningdisorder, impairment of cognitive processing speed, impairment ofacquisition of perceptual skills, impairment of acquisition of motorskills, and impairment of perceptual processing, comprising the stepsof:

(a) selecting a human or animal subject suffering from a symptomselected from the group consisting of memory impairment, a learningdisorder, impairment of cognitive processing speed, impairment ofacquisition of perceptual skills, impairment of acquisition of motorskills, and impairment of perceptual processing;

(b) applying to the vagus nerve of said human or animal subject astimulating electrical signal having parameters sufficient to alleviatesaid symptom of step (a);

(c) monitoring said human or animal subject via a method selected fromthe group consisting of a clinical test, a laboratory test,determination of clinical outcome, and combinations thereof, todetermine if said symptom of step (a) has been alleviated, or if furtherstimulation of said vagus nerve is required to alleviate said symptom;and

(d) if required, further stimulating said vagus nerve and monitoringsaid human or animal subject as in preceding steps (b) and (c),respectively, until said symptom has been alleviated.

A method of treating a human or animal subject suffering from persistentimpairment of consciousness, comprising the steps of:

(a) selecting a human or animal subject suffering from persistentimpairment of consciousness;

(b) applying to the vagus nerve of said human or animal subject astimulating electrical signal having parameters sufficient to alleviatesaid persistent impairment of consciousness;

(c) monitoring said human or animal subject via determination ofclinical outcome to determine if said persistent impairment ofconsciousness has been alleviated, or if further stimulation of saidvagus nerve is required to alleviate said persistent impairment ofconsciousness; and

(d) if required, further stimulating said vagus nerve and monitoringsaid human or animal subject as in preceding steps (b) and (c),respectively, until said persistent impairment of consciousness has beenalleviated.

Further scope of the applicability of the present invention will becomeapparent from the detailed description and drawings provided below.However, it should be understood that the detailed description andspecific examples, while indicating preferred embodiments of the presentinvention, are given by way of illustration only since various changesand modifications within the spirit and scope of the invention willbecome apparent to those skilled in the art from this detaileddescription.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features, and advantages of the presentinvention will be better understood from the following detaileddescription taken in conjunction with the accompanying drawings, all ofwhich are given by way of illustration only and which are not limitativeof the present invention, in which:

FIG. 1 is a bar graph showing the effect of vagus nerve stimulationgiven shortly after a learning experience, collapsed across Gamma andDelta Group patients. Eleven subjects silently read paragraphscontaining highlighted words. Word recognition performance was enhancedby vagus nerve stimulation delivered during the memory consolidationinterval. Stimulation intensity was 0.5 mA, biphasic pulses, 30 Hz.Highlighted words that were paired with vagus nerve stimulation wererecognized with greater frequency (t(9)=2.78, p<.03) than baselinecontrol words (not paired with stimulation).

FIG. 2 is a bar graph showing the effect of vagus nerve stimulation attolerance intensities for the Gamma Group. Subjects were tested 2 weeks,4 weeks and 16 weeks after implantation of the neurocyberneticprosthesis. Recognition performance of highlighted words followingstimulation was compared to baseline (no stimulation). Vagus nervestiumlation delivered during the memory consolidation intervalsignificantly enhanced retention performance only at Test 1 given 2weeks after implantation with a 0.5 mA intensity. Stimulation was rampedup to tolerance level after Test 2 and stimulation intensity averaged1.2 mA on Tests 2 and 3. It is unclear whether the decrement in themagnitude of the effect is due to the increased stimulation intensity orto a reduction in effect with the passage of time.

FIG. 3 is a camera lucida drawing of fos immunolabeling in the braininduced by vagus nerve stimulation for three hours (from FIG. 4 ofNaritoku et al. (1995) Epilepsy Research 22:53-62). The sections aredisplayed from caudal to rostal levels (left to right), with therelative abundance of labeled nuclei represented by the density of thedots in the drawings. Note the immunolabeling in the cingulate, andretrosplenial cortex, and in the amygdala. In the thalamus, there islabeling in the habenula, lateral posterior nucleus, and marginal zoneof the medial geniculate body, and in the hypothalamus there is labelingin the ventromedial and arcuate nuclei. In the brainstem there isimmunolabeling in the locus ceruleus, A5 nuclei and cochlear nuclei(Abbreviations: A5=A5 nucleus; Arc=arcuate nucleus; Cg=cingulate cortex;HbN=Habenular nucleus; LC=locus ceruleus; LPMC=Lateral postr thalamicnucleus; MZMG=marginal zone of medial geniculate; PMCO=postr medialcortical amygdalar nucleus; PVP=paraventricular nucleus of thalamus;RS=retrosplenial cortex; RSG=retrosplenial granular cortex; VC=ventralcochlear nucleus; VMH=ventromedial hypothalamic nucleus).

FIG. 4 is a graph showing the antiepileptogenic effect of vagus nervestimulation in the rat electrical kindling experiment described inExample 5.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description of the present invention is providedto aid those skilled in the art in practicing the same. Even so, thefollowing detailed description should not be construed to unduly limitthe present invention as modifications and variations in the embodimentsdiscussed herein may be made by those of ordinary skill in the artwithout departing from the spirit or scope of the present inventivediscovery.

The contents of each of the references cited in the presentspecification are herein incorporated by reference in their entirety.

Devices for Electrical Stimulation of the Vagus Nerve

The methods of the present invention rely upon modulated electricalstimulation of the vagus nerve. Such electrical stimulation can beachieved by a variety of different methods known in the art. By way ofexample, such electrical stimulation can be achieved via the use of aneurostimulating device which can be, but does not necessarily have tobe, implanted within the subject's body.

Forms of neurostimulating devices or accessories therefor that can beemployed in the methods disclosed herein are described in U.S. Pat. Nos.4,573,481; 4,702,254; 4,867,164; 4,920,979; 4,979,511; 5,025,807;5,154,172; 5,179,950; 5,186,170; 5,215,089; 5,222,494; 5,235,980,5,237,991; 5,251,634; 5,269,303; 5,304,206; and 5,351,394.

While the reader is referred to the disclosures of these documents fordetails of various neurostimulating devices useful in the presentmethods, certain aspects thereof can be summarized as follows for thereader's convenience.

The neurostimulator can utilize a conventional microprocessor and otherstandard electrical and electronic components, and in the case of animplanted device, communicates with a programmer and/or monitor locatedexternally to the subject's body by asynchronous serial communicationfor controlling or indicating states of the device. Passwords,handshakes, and parity checks can be employed for data integrity. Theneurostimulator also includes means for conserving energy, which isimportant in any battery operated device, and especially where thedevice is implanted for medical treatment, and means for providingvarious safety functions, such as preventing accidental reset of thedevice.

The stimulus generator can be implanted in the patient's body in apocket formed by the surgeon just below the skin in the chest in muchthe same manner as a cardiac pacemaker would be implanted, although aprimarily external neurostimulator can also be employed. Theneurostimulator also includes implantable stimulating electrodes,together with a lead system for applying the output signal of thestimulus generator to the patient's vagus nerve. Components external tothe patient's body include a programming wand for telemetry of parameterchanges to the stimulus generator and monitoring signals from thegenerator, and a computer and associated software for adjustment ofparameters and control of communication between the generator, theprogramming wand, and the computer.

In conjunction with its microprocessor-based logic and controlcircuitry, the stimulus generator can include a battery or set ofbatteries which can be of any reliable, long-lasting type conventionallyemployed for powering implantable medical electronic devices, such asthose employed in implantable cardiac pacemakers or defibrillators. In apreferred embodiment of the stimulus generator, the battery can be asingle lithium thionyl chloride cell. The terminals of the cell areconnected to the input side of a voltage regulator which smoothes thebattery output to produce a clean, steady output voltage, and providesenhancement thereof such as voltage multiplication or division ifrequired.

The voltage regulator supplies power to the logic and control section,which includes a microprocessor and controls the programmable functionsof the device. Among these programmable functions are output current,output signal frequency, output signal pulse width, output signalon-time, output signal off-time, daily treatment time for continuous orperiodic modulation of vagal activity, and output signal-start delaytime. Such programmability allows the output signal to be selectivelycrafted for application to the stimulating electrode set to obtain thedesired modulation of vagal activity. Timing signals for the logic andcontrol functions of the generator are provided by a crystal oscillator.

A built-in antenna enables communication between the implanted stimulusgenerator and the external electronics, including both programming andmonitoring devices, to permit the device to receive programming signalsfor parameter changes, and to transmit telemetry information from and tothe programming wand. Once the system is programmed, it can operatecontinuously at the programmed settings until they are reprogrammed bymeans of the external computer and the programming wand.

The logic and control section of the stimulus generator controls anoutput circuit or section which generates the programmed signal levelsappropriate for the condition being treated. The output section and itsprogrammed output signal are coupled (directly, capacitively, orinductively) to an electrical connector on the housing of the generatorand to a lead assembly connected to the stimulating electrodes. Thus,the programmed output signal of the stimulus generator can be applied tothe electrode set implanted on the subject's vagus nerve to modulatevagal activity in the desired manner.

The housing in which the stimulus generator is encased is hermeticallysealed and composed of a myaterial such as titanium, which isbiologically compatible with the fluids and tissues of the subject'sbody.

The implanted stimulus generator can be placed in the subject's chest ina cavity formed by the implanting surgeon just below the skin, much as apacemaker pulse generator would be implanted. A stimulating nerveelectrode set is conductively connected to the distal end of aninsulated electrically conductive lead assembly attached at its proximalend to a connector. The electrode set can be a bipolar stimulatingelectrode of the type described in U.S. Pat. No. 4,573,481. Theelectrode assembly is surgically implanted on the vagus nerve in thepatient's neck. The two electrodes are wrapped about the vagus nerve,and the assembly can be secured to the nerve by a spiral anchoringtether such as that disclosed in U.S. Pat. No. 4,979,511. The lead(s)is(are) secured, while retaining the ability to flex with movement ofthe chest and neck, by a suture connection to nearby tissue.

The stimulus generator can be programmed using a personal computeremploying appropriate software and a programming wand. The wand andsoftware permit non-invasive communication with the generator after thelatter is implanted, which is useful for both activation and monitoringfunctions. Programming capabilities should include the ability to modifythe adjustable parameters of the stimulus generator and its outputsignal, to test device diagnostics, and to store and retrievetelemetered data.

Diagnostics testing should be implemented to verify proper operation ofthe device. The nerve electrodes are capable of indefinite use absentindication of a problem with them observed on such testing.

Although an implantable device for vagus nerve stimulation has beendescribed, it will be apparent to those skilled in the art from theforegoing description that variations and modifications thereof can bereadily made. For example, rather than employing a totally implantabledevice, one can employ an electronic energization package that isprimarily external to the body. Stimulation can be achieved with an RFpower device implemented to provide the necessary energy level. Theimplanted components may be limited to the lead/electrode assembly, acoil, and a DC rectifier. Pulses programmed with the desired parameterswould be transmitted through the skin with an RF carrier, and the signalthereafter rectified to regenerate a pulsed signal for application asthe stimulus to the vagus nerve to modulate vagal activity. This wouldvirtually eliminate the need for battery changes.

An external stimulus generator can be employed, with leads extendingpercutaneously to the implanted nerve electrode set.

EXAMPLE 1 Modulation of Brain Neural Plasticity by Vagus NerveStimulation

As noted above, the concept of neural plasticity encompasses structuralalterations in the brain that lead to changes in neural function.Changes in neural function then lead to changes in behavior, or in thecapacity or potential for behavior.

The present inventors have concluded that brain neural plasticity inhumans and animals can be modulated by vagus nerve stimulation by thefollowing steps:

(a) applying to the vagus nerve of said human or animal a stimulatingelectrical signal having parameters sufficient to cause a physiological,structural, or neuronal connective alteration in the brain;

(b) changing neural function in said brain as a consequence of saidalteration; and

(c) changing behavior or the capacity for behavior in said human oranimal subject.

Specifically, brain neural plasticity can be modulated as follows.

Apparatus

The neurostimulating device and electrodes can be implanted as describedin U.S. Pat. Nos. 5,154,172 and 5,269,303, although any conventionaldevices known in the art can be employed.

Stimulation Parameters of the Output Signal

The preferred range of stimulation parameters of the output signal ofthe stimulus generator for modulation of brain neuroplasticity, and thetypical value of each parameter of the output signal programmed into thedevice can be as follows.

The pulse width can be in the range of from about 50 μsec. to about1,500 μsec., preferably from about 100 μsec. to about 1,000 μsec., morepreferably from about 250 μsec. to about 750 μsec., even more preferablyfrom about 400 μsec. to about 750 μsec., and most preferably from about400 μsec. to about 600 μsec. A pulse width of about 400 μsec. to about750 μsec. is appropriate when C fiber activation is required or desired.If only A and B fiber activation is required or desired, then a pulsewidth of about 50 μsec. to about 250 μsec. would be effective. The typeof fiber activation can vary between individual patients.

The output current can be in the range of from about 0.1 mA to about 10mA, more preferably from about 0.1 mA to about 6 mA, most preferablyfrom about 0.1 mA to about 4 mA.

The frequency of the output signal can be in the range of from about 1Hz to about 75 Hz, more preferably about 5 Hz to about 60 Hz, mostpreferably from about 10 Hz to about 40 Hz.

The pulses can be monophasic, biphasic, or a combination thereof.

The train duration of the output current can be in the range of fromabout 1 sec. to about 4 hours, more preferably from about 2.5 sec. toabout 2.5 hours, most preferably from about 5 sec. to about 1 hour. Theinterval between trains can be in the range of from about 1 sec. toabout 1 week, more preferably from about 1 sec. to about 1 day, mostpreferably from about 5 sec. to about 4 hours. Trains can also besupplied on demand.

As will be recognized by those of ordinary skill in the art, any or allof the foregoing vagus nerve stimulation parameters can be titratedclinically to achieve the desired response in a patient.

EXAMPLE 2 Improvement of Memory and Learning by Vagus Nerve Stimulation

Methods and Design

Learning Experiences

The learning experiences to which the methods described herein can beapplied include those which are physical, mental, or a combinationthereof. As discussed above, learning and memory, one form of neuralplasticity, can take many forms. Most commonly, memories are classifiedas being either procedural or declarative. Further, there are a numberof different aspects to each kind of memory. Procedural learning andmemory, characterized as knowing how to perform some act, can includethe learning and remembering of motor skills, perceptual abilities, andcognitive capabilities. Declarative learning and memory, knowingspecific kinds of factual information, can include the knowledge ofisolated and connected facts, the events and episodes of one's lifetime,and the routes and pathways of everyday life. As noted supra, each ofthese kinds of memory is the result of neural plasticity taking place inthe brain, and because each can be modulated by peripherallyadministered chemical agents which do not cross the blood-brain barrier,their mode of action is likely to be through the action of receptors inthe viscera that trigger nerve impulses which travel along the vagusnerve to targets in the brain. Hence, the storage of these forms ofmemory can be modulated by direct stimulation of the vagus nerve,bypassing the need to activate neural receptors in the viscera.

Apparatus

The device and electrodes can be implanted as described in U.S. Pat.Nos. 5,154,172 and 5,269,303, although any comparable device known inthe art can be employed.

Stimulation Parameters of the Output Signal

Vagus nerve stimulation subsequent to exposure of a human or animalsubject to a learning experience in order to improve learning or memoryin that subject can be performed by employing a range of stimulationparameter values of the output signal of the stimulus generator.

The pulse width can be in the range of from about 50 μsec. to about1,500 μsec., preferably from about 100 μsec. to about 1,000 μsec., morepreferably from about 250 μsec. to about 750 μsec., even more preferablyfrom about 400 μsec. to about 750 μsec., and most preferably from about400 μsec. to about 600 μsec. A pulse width of about 400 μsec. to about750 μsec. is appropriate when C fiber activation is required or desired.If only A and B fiber activation is required or desired, then a pulsewidth of about 50 μsec. to about 250 μsec. would be effective. The typeof fiber activation can vary between individual patients.

The output current employed for the signal should be of a moderate orintermediate intensity, and can be in the range of from about 0.1 mA toabout 10 mA, more preferably from about 0.1 mA to about 6 mA, mostpreferably from about 0.1 mA to about 4 mA.

The frequency of the output signal can be in the range of from about 1Hz to about 75 Hz, more preferably about 5 Hz to about 60 Hz, mostpreferably from about 10 Hz to about 40 Hz.

The output signal can be monophasic, biphasic, or a combination thereof.

The train duration of the output current can be in the range of fromabout 1 sec. to about 4 hours, more preferably from about 2.5 sec. toabout 2 hours, more preferably from about 5 sec. to about 1 hour, andmost preferably about 30 sec. The interval between trains can be in therange of from about 1 sec. to about 60 sec., more preferably from about2.5 sec. to about 45 sec., most preferably from about 5 sec. to about 30sec.

The time period after exposure of the human or animal subject to alearning experience in which electrical stimulation of the vagus nerveto improve memory or learning can occur can be in the range of fromabout 0.01 sec. to about 30 min., more preferably about 0.05 sec. toabout 20 min., most preferably about 0.1 sec. to about 15 min. Thememory consolidation period in humans typically lasts for 30 minutesafter the conclusion of acquisition.

As will be recognized by those of ordinary skill in the art, any or allof the foregoing vagus nerve stimulation parameters can be titrated byroutine experimentation to achieve the desired memory enhancementresponse in a particular subject.

The improved storage of the memory or retention of the learningexperience can be observed hours, days, weeks, months, or years afterexposing or subjecting a human or animal subject to the learningexperience.

Stimuli and Tests for Human Testing

Fourteen narrative paragraphs were used as stimuli in this experiment.Each paragraph was approximately 200 words in length, of appropriatereading level for each subject, and each was typed on a separate page.When presented to the subjects, each paragraph was covered with acardboard mask that revealed only two lines of text at a time. Subjectswere instructed to read at a comfortable pace and to move the mask downthe page as the paragraph was read. Subjects were told that they wouldbe questioned about the paragraphs later, and that the mask was beingused to prevent reviewing of the material. Two versions of eachparagraph were prepared. In one version, seven words were highlightedusing a yellow marking pen, and subjects were told that a memory testfor these words would follow questions about the paragraph. In the otherset of paragraphs, no words were highlighted. Words chosen forhighlighting were common nouns, and were distributed equally throughouteach paragraph.

In each block of seven paragraphs, the first paragraph was shorter andsimpler than the subsequent paragraphs, and served as a warm-upparagraph. Data from these warm-up paragraphs were not included in theanalysis.

For the six test paragraphs in each block, three "loaded" paragraphs(paragraphs with highlighted words to be remembered) were alternatedwith three "unloaded" paragraphs (no highlighted words). In addition, inone of the two blocks of paragraphs, stimulation of the vagus nerveoccurred, while in the other block, the loaded trials were notassociated with vagus nerve stimulation. Whether vagus nerve stimulationoccurred in the first or second block of paragraphs was counterbalancedacross subjects. The overall design of this experiment is summarized inTable 1.

                                      TABLE 1                                     __________________________________________________________________________    Summary of Experimental Design                                                1   2  3 4  5 6  7 Break                                                                            8 9  10                                                                              11 12                                                                              13 14                                       __________________________________________________________________________    1 X A  B C  D E  F    X G  H I  J K  L                                        2 X B  A D  C F  E    X H  G J  I L  K                                        3 X A  B C  D E  F    X G  H I  J K  L                                        4 X B  A D  C F  E    X H  G J  I L  K                                        __________________________________________________________________________

Letters A-L and X represent the paragraphs of text that were read by thesubjects; rows represent the four condition orders. Underlines indicatethat highlighted word was present in the paragraphs; italics indicatethat stimulation of the vagus nerve was given following reading of theparagraph. Subjects were assigned to an experimental is condition viaLatin-square rotation.

Procedure for Human Testing

Each subject was given a brief summary of the procedure used in thisstudy at each visit (i.e., visits 2, 5, and 7), and any questions wereanswered prior to testing. Visit 2 testing served as a pre-implantationbaseline consisting of paragraph reading followed by inferential,logical, and retention queries. The procedures for this visit wereidentical to those discussed below for visits 5 and 7, except that vagusnerve stimulation was not administered. The first series (5stimulations) of vagus nerve stimulations were given to subjects duringvisit 5 at an intensity of 0.5 mA with a frequency of 30 Hz (Gamma) orminimal perceptible current (0.25-1 mA) at 1 Hz (Delta). During thistime, the reaction of the subject was studied, and appropriateadjustments were made. This enabled each subject to become acquaintedwith the sensations produced by the stimulation, and helped to minimizepossible effects of novelty produced by the sensations associated withstimulation. It is important to eliminate any novelty effects producedby the stimulation.

At that time, during Visit 5, those subjects in the Gamma Group receivedvagus nerve stimulation at 0.5 mA, 30 Hz. Those in the Delta Groupreceived threshold stimulation to perception (0.25 to 1.0 mA) once every180 minutes. Following stimulation, a one-hour rest period was given toensure that any residual effects resulting from these first exposures tothe stimulation current were minimized before memory testing proceduresbegan. Ramping procedures began following completion of the memorytesting procedure on Visit 5.

Following the one-hour rest period, subjects were asked to read apractice paragraph (paragraph X in Table 1) to familiarize them with theuse of the cardboard mask during reading. A two-minute rest periodfollowed to allow dissipation of any arousal that might have occurred.Pulse rate and blood pressure were measured at the end of this restperiod. The two blocks of six paragraphs each were then administered.There was a five-minute rest period following administration of thefirst block of paragraphs and the beginning of the second. A warm-upparagraph was also given at the start of the second block of paragraphs.Immediately following completion of each paragraph, pulse rate and bloodpressure were recorded and two questions, one factual and onelogical-inferential, were asked about the content of that paragraph. Inaddition, for the loaded paragraphs, subjects were asked to recall thehighlighted words following answering of the two questions. For thoseparagraphs to be paired with vagus-nerve stimulation, immediately aftereach subject in the Gamma Group completed reading the paragraph andanswering the questions, she/he was given vagus nerve stimulation forsec. Those subjects in the Delta Group received no stimulation.

Following completion of the final paragraph and the answering ofquestions, an unannounced recognition test of all highlighted words wasgiven. In this test, a list of all 42 highlighted target words wasrandomly interspersed with 210 distractor words (16.6% target words).The distractor words were highly concrete imageable nouns (Pavio et al.(1968). Concreteness, imagery, and meaningfulness values for 925 nouns.Journal of Experimental Psychology, 76, (Suppl), 1-25). Subjects wereasked to mark all words which they believed had been previouslypresented as highlighted words in the paragraphs they had read earlier.When this test was completed, pulse rate and blood pressure weremeasured and the ramp-up or ramp-down procedure was resumed.

Subjects were again tested during Visit 7 according to the basicprocedures described above for Visit 5. This time, however, vagus nervestimulation given after the reading of half the paragraphs was for thesubjects in the Gamma Group at the tolerance intensity that each hadbeen ramped up to. This ranged from 0.75 mA to 1.5 mA. A final test wasconducted on Visit 9. This time, subjects in the Gamma Group receivedvagus nerve stimulation at their individual tolerance intensity (0.75 mAto 1.5 mA), while all subjects in the Delta Group received stimulationat 0.5 mA.

This experimental design enables each subject to establish his/her ownbaseline against which stimulation effects are measured. Eachstimulation group provided a standard of comparison to evaluate thegeneral effects of device implantation and vagus nerve stimulation onmemory performance. This is crucial as the pre-implantation baselinemeasures (Visit 4) rules out changes in performance merely resultingfrom surgery or the presence of the device. The pre-implantationbaseline is not in itself an adequate control for cognitive testingwithout an additional post-implantation stimulation baseline. Thiscontrol was provided by paragraph reading followed by no vagus nervestimulation in each group. Further, this experimental design permits thecomparison of the effects of different current intensity levels. Onehalf of the patients (those in the Gamma Group) were treated with 0.5 mAstimulation during Visit 5. The other half of the patients (the DeltaGroup) received no stimulation at either Visit 5 or Visit 7. On Visit 7,patients in the Gamma Group had their stimulation intensity increased totheir own individual tolerance level, not exceeding the ceilingintensity of 1.5 mA. Stimulation intensity is an important factor as theresults from laboratory animal studies (Clark et al. (1994) Society forNeuroscience Abstracts 20:802; Clark et al. (1995) Neurobiology ofLearning and Memory 63:213-216) indicate that this is an importantparameter. In that case, only 0.4 mA stimulation produced significantenhancement in retention performance. Lastly, if vagus nerve stimulationhas a capacity to improve memory or other cognitive functions in humans,it is most likely to do so for those specific events occurring during aninterval time-locked to the stimulus. The vagus nerve stimulationstimulus selectively enhances certain information over the milieu ofother information during the memory consolidation period.

General neuropsychological tests for cognitive and memory performanceare not designed to evaluate the time-locked pairing of salient cues(i.e., vagus nerve stimulation-induced arousal) with the acquisition ofinformation. Therefore, any memory-modulating effect would be overlookedor masked (i.e., a lowered mean retention performance) by retentionqueries for acquired information other than that associated with ortime-locked to vagus nerve stimulation. The working memory paradigmdescribed above is, in contrast, sensitive to even subtle vagus nervestimulation influences on the formation of memories, since retention forwords time-locked to vagus nerve stimulation at three differentintensities are compared to retention for words time-locked to no vagusnerve stimulation.

RESULTS

Recognition memory performance of eleven patients was analyzed in testsperformed on Visits 5, 7, and 9 (two, four, and sixteen weekspostimplantation, respectively) The results are summarized in FIGS. 1and 2.

Current Intensity at 0.5 mA

FIG. 1 shows the effect of vagus nerve stimulation (0.5 mA, 0.5 ms pulsewidth, 30 Hz), given shortly after a learning experience, collapsedacross Gamma- and Delta-group patients. To counterbalance for timeeffects, patients (n=5) in the Gamma group received the above mentionedstimulus at Visit 5 while those patients (n=6) in Delta group receivedthe identical stimulation at Visit 9. Each subject read a series ofparagraphs, some of which contained highlighted words. In half thetrials, reading a paragraph with highlighted words was followed by vagusnerve stimulation. In the other half of the trials, no stimulation wasgiven. Retention performance, measured as recognition of highlightedwords, showed that subjects remembered more words from trials that werefollowed by vagus nerve stimulation than they did in those trials inwhich no stimulation followed reading of the paragraphs (t(9)=2.78,p<0.025). These data indicate that regardless of the time after deviceimplantation, vagus nerve stimulation at 0.5 mA, when administered aftera learning experience, significantly enhanced retention performance ofthe learned material.

Current Intensity at Subject Tolerance

At Visits 7 and 9, patients in the Gamma group received vagus nervestimulation at each individual's tolerance intensity (e.g., 0.75 to 1.5mA). FIG. 2 shows the effect of vagus nerve stimulation at toleranceintensities for the Gamma group. Vagus nerve stimulation given attolerance intensities (0.75 to 1.5 mA) shortly after a learningexperience did not significantly enhance recognition performance(t(9)=0.76, p<0.470). This finding parallels those effects observed foranimals in the inventors' laboratory (Clark et al. (1994) Society forNeuroscience Abstracts 20:802; Clark et al. Neurobiology of Learning andMemory 63:213-216). Animals that received posttraining administration ofvagus nerve simulation showed significantly enhanced memory performanceat moderate current intensities (i.e. 0.4 mA), but not at thecomparatively higher stimulation intensity of 0.8 mA. Such aninput-output curve is analogous to the inverted U-shaped dose responsecurves commonly found for memory modulating drugs. Thus, these findingswith human subjects suggest that vagus nerve stimulation producesenhancement of memory storage processes in a manner similar to that ofother memory modulatory agents.

EXAMPLE 3 Treatment of Traumatic Brain Injury by Vaous Nerve Stimulation

Vagus nerve stimulation is expected to help sufferers of traumatic braininjury in a number of ways.

First, vagus nerve stimulation induces increased neuronal activity inwidespread regions of the brain (Naritoku et al. (1995) EpilepsyResearch 22:53-62). Such stimulation can ameliorate the problems ofbrain hypometabolism and decrease in brain activity induced by braininjury, and aid in improving recovery of cognition, motor skills,activities of daily living, and memory.

Secondly, vagus nerve stimulation activates the protein fos in brainneurons (Naritoku et al., supra). Since this protein promotes subsequenttranscription and translation of genes, thereby increasing theproduction of cellular proteins, it enhances brain neural plasticity andthereby contributes to recovery from injury.

Thirdly, vagus nerve stimulation produces widespread increases ofmonoamines in the brain, including the neuro-transmitters serotonin andnorepinephrine. Several studies indicate that increases in monoaminesare antiepileptogenic, i.e, prevent epilepsy (Gellman et al. (1987) J.Pharmacol. Exp. Ther. 241:891-898). While drugs that increasemonoamines, such as amphetamines, cause undesired side effects, vagusnerve stimulation represents a means of increasing monoaminetransmission without negative side effects.

Next, vagus nerve stimulation will aid in preventing the development ofepilepsy. Previous investigations on vagus nerve stimulation haveexamined the treatment of established chronic epilepsy. The methodsdisclosed herein are expected to be useful in preventing the developmentof epilepsy itself. Several types of data support this hypothesis.

First, at least part of the anti-seizure properties of vagus nervestimulation relates to activation of monoaminergic nuclei. Krahl et al.((1994) Society for Neuroscience Abstracts 20:1453) have demonstratedthat inactivation of monoaminergic nuclei reduces the effectiveness ofvagus nerve stimulation. Furthermore, the data of Naritoku et al.((1995) Epilepsy Res. 22:53-62) demonstrate that vagus nerve stimulationactivates the A5 and locus ceruleus noradrenergic nuclei.

Secondly, increasing monoaminergic transmission prevents the developmentof epilepsy in animals (Jobe et al. (1981) Biochem. Pharmacol.30:3137-3144). This property has been termed "lantiepileptogenic," asopposed to "antiepileptic" or "anticonvulsant". An antiepilepto-genictherapy is distinctly different from antiepileptic or anticonvulsanttherapies in that the latter two therapies prevent seizures onceepilepsy is established, but do not prevent the development of epilepsy,as do antiepilepto-genic therapies. The effects of vagus nervestimulation will prevent the processes that cause epilepsy.Specifically, injections of high amounts of monoaminergic drugs such asclonidine block the rate at which epilepsy can be established in animalmodels using the kindling protocol, which involves direct applicationsof small amounts of electrical currents to limbic structures (Burchfielet al. (1989) Neurosci. Behav. Rev. 13:289-299; Gellman et al. (1987) J.Pharmacol. Exp. Ther.241:891-898).

Thirdly, increases in serotonin or norepinephrine brought about by drugssuch as fluoxetine reduce spontaneous and induced seizures in animalsand humans (Jobe et al. (1973) J. Pharmacol. Exp. Ther. 184:1-10;Leander (1992) Epilepsia 33:573-576; Favale et al. (1995) Neurology45:1926-1927).

Finally, vagus nerve stimulation is expected to improve memory inbrain-injured patients. As demonstrated in Example 1, supra, vagus nervestimulation improves memory function in normal human subjects.

Methods and Design

Types of Brain Injuries Amenable to Treatment by Vagus Nerve Stimulation

Vagus nerve stimulation can be used to improve recovery of patientssuffering from traumatic brain injury such as that incurred, forexample, from blows to the head from various objects; penetratinginjuries from missiles, bullets, shrapnel, etc., falls; skull fractureswith resulting penetration by bone pieces; sudden acceleration ordeceleration injuries; and other causes well known in the art. Exemplarysymptoms of such brain injuries include, but are not limited to,impaired level of consciousness, impaired cognition, impaired cognitiveprocessing speed, impaired language, impaired motor activity, impairedmemory, impaired motor skills, and impaired sensory skills.

Apparatus

The device and electrodes can be implanted as described in U.S. Pat.Nos. 5,154,172 and 5,269,303, although any conventional devices known inthe art can be employed.

Stimulation Parameters of the Output Signal

The preferred range of stimulation parameters of the output signal ofthe stimulus generator for treatment of traumatic brain injury, and thetypical value of each parameter of the output signal programmed into thedevice by the attending physician or therapist, can be as follows.

The pulse width can be in the range of from about 50 μsec. to about1,500 μsec., preferably from about 100 μsec. to about 1,000 μsec., morepreferably from about 250 μsec. to about 750 μsec., even more preferablyfrom about 400 μsec. to about 750 μsec., and most preferably from about400 μsec. to about 600 μsec. A pulse width of about 400 μsec. to about750 μsec. is appropriate when C fiber activation is required or desired.If only A and B fiber activation is required or desired, then a pulsewidth of about 50 μsec. to about 250 μsec. would be effective. The typeof fiber activation can vary between individual patients.

The output current can be in the range of from about 0.1 mA to about 10mA, more preferably from about 0.1 mA to about 6 mA, most preferablyfrom about 0.1 mA to about 4 mA.

The frequency of the output signal can be in the range of from about 1Hz to about 75 Hz, more preferably about 5 Hz to about 60 Hz, mostpreferably from about 10 Hz to about 40 Hz.

The pulses can be monophasic, biphasic, or a combination thereof.

The train duration of the output current can be in the range of fromabout 1 sec. to about 4 hours, more preferably from about 2.5 sec. toabout 2.5 hours, most preferably from about 5 sec. to about 1 hour. Theinterval between trains can be in the range of from about 1 sec. toabout 1 week, more preferably from about 1 sec. to about 1 day, mostpreferably from about 5 sec. to about 4 hours. Trains can also besupplied on demand if this is determined to be preferable by thephysician or therapist.

The stimulating electrical signal can be applied to the vagus nerve anytime after appearance of any of the symptoms noted above, for example,within a time period of from about 1 hour to about 3 months afterappearance of the symptom.

Finally, the duration of the total therapy can vary depending upon thenature and severity of the brain injury, as well as the physicalattributes and condition of the patient. Therapy can vary from about oneday to as long as continued clinical improvement is obtained or desired,e.g., several months or years to the remainder of the patient's life.The necessity for, or desirability of, further therapy can be determinedfrom results obtained via administering a variety of different clinicalor laboratory tests to the patient. Examples of useful clinical testsinclude tests of activities required for daily living, memory,cognition, motor skills, development of epilepsy, FIM (Functional IndexMeasurement) scores, and other standardized measurements of functionaloutcome. Examples of useful laboratory tests include a brain scan, a PETscan, a SPECT scan, an EEG, an evoked potential, monitoring the level ofa neurotransmitter such as norepinephrine, serotonin, or dopamine, ormetabolites thereof, in the brain, and monitoring the level of aneurotransmitter in spinal fluid.

As will be recognized by those of ordinary skill in the art, any or allof the foregoing vagus nerve stimulation parameters can be titratedclinically to achieve the desired response in a patient.

EXAMPLE 4 Prevention of Eilepsy by Vapus Nerve Stimulation

As noted above in Example 3, various types of data lead to theconclusion that vagus nerve stimulation is expected to be effective inpreventing the development of epilepsy. Such therapy is applicable notonly in the treatment of patients suffering from traumatic brain injury,but also in preventing the development of epilepsy in other subjectsprone to this disorder. This population includes patients predisposedto, or rendered susceptible to, developing epilepsy. These patientsinclude, for example, those suffering from a disease or condition suchas traumatic brain injury, post-encephalitic patients, post-strokepatients, and patients having a family history or genetic backgroundpredisposing them to developing epilepsy.

Methods and Design

Apparatus

The device and electrodes can be implanted as described in U.S. Pat.Nos. 5,154,172 and 5,269,303, although any conventional devices known inthe art can be employed.

Stimulation Parameters of the Output Signal

The preferred range of stimulation parameters of the output signal ofthe stimulus generator for the prevention of epilepsy, and the typicalvalue of each parameter of the output signal programmed into the deviceby the attending physician or therapist, can be as follows.

The pulse width can be in the range of from about 50 μsec. to about1,500 μsec., preferably from about 100 μsec. to about 1,000 μsec., morepreferably from about 250 μsec. to about 750 μsec., even more preferablyfrom about 400 μsec. to about 750 μsec., and most preferably from about400 μsec. to about 600 μsec. A pulse width of about 400 μsec. to about750 μsec. is appropriate when C fiber activation is required or desired.If only A and B fiber activation is required or desired, then a pulsewidth of about 50 μsec. to about 250 μsec. would be effective. The typeof fiber activation can vary between individual patients.

The output current can be in the range of from about 0.1 mA to about 10mA, more preferably from about 0.1 mA to about 6 mA, most preferablyfrom about 0.1 mA to about 4 mA.

The frequency of the output signal can be in the range of from about 1Hz to about 75 Hz, more preferably about 5 Hz to about 60 Hz, mostpreferably from about 10 Hz to about 40 Hz.

The pulses can be monophasic, biphasic, or a combination thereof.

The train duration of the output current can be in the range of fromabout 1 sec. to about 4 hours, more preferably from about 2.5 sec. toabout 2.5 hours, most preferably from about 5 sec. to about 1 hour. Theinterval between trains can be in the range of from about 1 sec. toabout 1 week, more preferably from about 1 sec. to about 1 day, mostpreferably from about 5 sec. to about 4 hours. Trains can also besupplied on demand if this is determined to be preferable by thephysician or therapist.

Finally, the duration of the total therapy can vary depending upon thenature and severity of the underlying disorder or condition, as well asthe physical attributes and condition of the patient. Therapy can varyfrom about one day or one year to as long as continued clinicalimprovement is obtained or desired, e.g., several months or years to theremainder of the patient's life. In the case of preventing epilepsy, thetotal duration of therapy can be in the range of from about one day toas long as necessary to prevent development of epilepsy in the patient.Monitoring of patients for clinical improvement can be performed byconducting a procedure selected from an electroencephalogram, an evokedpotential, spectral mapping, voltage mapping, clinical assessment, andcombinations thereof.

As will be recognized by those of ordinary skill in the art, any or allof the foregoing vagus nerve stimulation parameters can be titratedclinically to achieve the desired response in a patient.

EXAMPLE 5 Antiepileptogenic Effect of Vagus Nerve Stimulation in a RatElectrical Kindling Model

Electrical kindling is an important model of epileptogenesis, i.e., thedevelopment of a chronic seizure focus. Since repeated kindling sessionscause progressive increases in severe seizure severity (Goddard et al.(1969) Exp. Neurol. 25:295-330), electrical kindling can be utilized totest for antiepileptogenic properties of a given therapy (Schmutz et al.(1988) J. Neural. Transm. 72:245-257; Silver et al. (1991) Ann. Neurol.29:356-363). The effectiveness of vagus nerve stimulation in opposingepileptogenesis was therefore investigated using this paradigm.

Experimental

Electrodes were implanted on the left vagus nerve of adult maleSprague-Dawley rats (250-300 g) to provide vagus nerve stimulation. Atwisted pair depth electrode was implanted into the right amygdala(coordinates from bregma: AP -2.4 mm; ventral -8.6 m; lateral -4.2 mm)using a stereotaxic device, and the animals were allowed to recuperatefor at least one week.

On the first day, the kindling threshold was determined by applying 100Hz biphasic square wave pulses to the depth electrode for 30 sec. Thecurrent was increased in 10 μA increments until at least a 10 sec.aferdischarge was obtained. The resulting threshold current was recordedfor each animal and used for subsequent sessions. Prior to each kindlingsession, vagus nerve stimulation (1 mA/30 Hz/500 μsec. biphasic squarepulses) or sham stimulation (i.e., identical handling, no vagus nervestimulation) was administered for one hour. Subsequently, daily kindlingstimuli were administered through the depth electrode (biphasic squarewave, 100 Hz). Seizures were scored on a standard severity scale(Racine, R. J. (1972) Electroencephalogr. Clin. Neurophysiol. 32:281) ona scale from 0 to 5, in which 5 represents a fully kindled convulsiveseizure. The results are shown in FIG. 4.

Results

As can be seen in FIG. 4, there were significant differences in theprogression of kindling stage for rats that received vagus nervestimulation pretreatment (-▪-, n=4), control animals that did notreceive vagus nerve stimulation (--, n=5), and a third comparison group(-▴-, n=7) that received vagus nerve stimulation for the first 6 days,but not for subsequent kindling sessions (p=0.0001; repeated measuresANOVA).

Post-hoc analysis revealed that there was a significant delay in animalsthat received vagus nerve stimulation compared to control animals (p≦0.01; Newman-Keuls test). The mean stimuli to class 5 seizures was 11.3±1.5 (days ±SD) in vagus nerve stimulation-treated animals (-▪-)compared to 6.0 ±1.2 in sham-treated animals (--; p=0.001; t-test).

To assure that the treatment opposed epileptogenesis rather than maskingthe resulting seizure, the third group received vagus nerve stimulationfor 6 kindling sessions, and then received no vagus nerve stimulationduring subsequent sessions. This is shown by the middle curve (-▴-) inFIG. 4. As expected, the rate of kindling in this group was similar tothat in the other treated group that received the first six vagus nervestimulations (-▪-). If vagus nerve stimulation was simply masking theseizure severity, the severity score would be expected to increase tocontrol values for the remaining kindling sessions. However, the seizureseverity scores remained significantly lower than those in controlanimals (p ≦0.01, Neuman-Keuls test), and exhibited an intermediateprogression of severity increases. These results demonstrate that thevagus nerve stimulation opposed, rather than masked, epileptogenesis.

In summary, these kindling experiments indicate that vagus nervestimulation can oppose epileptogenesis, and may therefore be a usefultherapy to prevent the development of epilepsy in clinical situationsassociated with a high risk for developing epilepsy.

EXAMPLE 6 Treatment of Memory Disorders and Chronic Memory Impairment byVaaus Nerve Stimulation

Electrical stimulation of the vagus nerve can also is be used intherapies to treat subjects suffering from diseases or conditions inwhich memory impairment or learning disorders are a prominent feature.Examples of such diseases or conditions include Alzheimer's Disease,Binswanger Disease, Pick's Disease, Parkinson's Disease, cerebral palsy,post-meningitis, post-encephalitis, traumatic brain injury,Wernicke-Korsakoff syndrome, alcohol-related memory disorders,post-temporal lobectomy, memory loss from multi-infarct (stroke) state,multiple sclerosis, post-cardiac arrest injury, post-hypoxic injury, andnear drowning.

Electrical stimulation of the vagus nerve can also be used in therapiesto treat subjects suffering from disorders in which impairment ofcognitive processing speed, acquisition of perceptual skills,acquisition of motor skills, or perceptual processing are a prominentfeature.

Examples of these diseases or conditions include mental retardation,multiple sclerosis, perinatal asphyxia, intrauterine infections,cerebral palsy, post-meningitis, post-encephalitis, dyslexia,constructional apraxia, post-cardiac arrest injury, post-hypoxic injury,multi-infarct (stroke) state, and near drowning.

Methods and Design

Apparatus

The device and electrodes can be implanted as described in U.S. Pat.Nos. 5,154,172 and 5,269,303, although any conventional devices known inthe art can be employed.

Stimulation Parameters of the Output Signal

The preferred range of stimulation parameters of the output signal ofthe stimulus generator for the treatment of memory impairment, learningdisorders, impairment of cognitive processing speed, acquisition ofperceptual skills, acquisition of motor skills, or perceptualprocessing, and the typical value of each parameter of the output signalprogrammed into the device by the attending physician or therapist, canbe as follows.

The pulse width caq be in the range of from about 50 μsec. to about1,500 μsec., preferably from about 100 μsec. to about 1,000 μsec., morepreferably from about 250 μsec. to about 750 μsec., even more preferablyfrom about 400 μsec. to about 750 μsec., and most preferably from about400 μsec. to about 600 μsec. A pulse width of about 400 μsec. to about750 μsec. is appropriate when C fiber activation is required or desired.If only A and B fiber activation is required or desired, then a pulsewidth of about 50 μsec. to about 250 μsec. would be effective. The typeof fiber activation can vary between individual patients.

The output current can be in the range of from about 0.1 mA to about 10mA, more preferably from about 0.1 mA to about 6 mA, most preferablyfrom about 0.1 mA to about 4 mA.

The frequency of the output signal can be in the range of from about 1Hz to about 75 Hz, more preferably about 5 Hz to about 60 Hz, mostpreferably from about 10 Hz to about 40 Hz.

The pulses can be monophasic, biphasic, or a combination thereof.

The train duration of the output current can be in the range of fromabout 1 sec. to about 4 hours, more preferably from about 2.5 sec. toabout 2.5 hours, most preferably from about 5 sec. to about 1 hour. Theinterval between trains can be in the range of from about 1 sec. toabout 1 week, more preferably from about 1 sec. to about 1 day, mostpreferably from about 5 sec. to about 4 hours. Trains can also besupplied on demand if this is determined to be preferable by thephysician or therapist.

The stimulating electrical current can be applied to the vagus nerve anytime after appearance of the symptom(s) to be treated.

Finally, the duration of the total therapy can vary depending upon thenature and severity of the disorder, condition, or impairment, as wellas the physical attributes and condition of the patient. Therapy canvary from about one day to as long as continued clinical improvement isobtained or desired, e.g., several months or years to the remainder ofthe patient's life. Clinical tests that can be employed to monitor thesuccess of therapy include standard neuropsychological tests such asWISC, WAIS, Halsted-Reitan, and combinations thereof. Useful laboratorytests include, for example, electroencephalograms, evoked potentials,spectral mapping, voltage mapping, clinical assessment, and combinationsthereof.

As will be recognized by those of ordinary skill in the art, any or allof the foregoing vagus nerve stimulation parameters can be titratedclinically to achieve the desired response in a patient.

EXAMPLE 7 Treatment of Persistent Impairment of Consciousness by VacusNerve Stimulation

The present inventors have also concluded that vagus nerve stimulationcan be employed in the treatment of persistent impairment ofconsciousness, such as that associated with coma or vegetative states.

Methods and Design

Apparatus

The device and electrodes can be implanted as described in U.S. Pat.Nos. 5,154,172 and 5,269,303, although any conventional devices known inthe art can be employed.

Stimulation Parameters of the Output Signal

The preferred range of stimulation parameters of the output signal ofthe stimulus generator for the treatment of persistent impairment ofconsciousness, and the typical value of each parameter of the outputsignal programmed into the device by the attending physician ortherapist, can be as follows.

The pulse width can be in the range of from about 50 μsec. to about1,500 μsec., preferably from about 100 μsec. to about 1,000 μsec., morepreferably from about 250 μsec. to about 750 μsec., even more preferablyfrom about 400 μsec. to about 750 μsec., and most preferably from about400 μsec. to about 600 μsec. A pulse width of about 400 μsec. to about750 μsec. is appropriate when C fiber activation is required or desired.If only A and B fiber activation is required or desired, then a pulsewidth of about 50 μsec. to about 250 μsec. would be effective. The typeof fiber activation can vary between individual patients.

The output current can be in the range of from about 0.1 mA to about 10mA, more preferably from about 0.1 mA to about 6 mA, most preferablyfrom about 0.1 mA to about 4 mA.

The frequency of the output signal can be in the range of from about 1Hz to about 75 Hz, more preferably about 5 Hz to about 60 Hz, mostpreferably from about 10 Hz to about 40 Hz.

The pulses can be monophasic, biphasic, or a combination thereof.

The train duration of the output current can be in the range of fromabout 1 sec. to about 4 hours, more preferably from about 2.5 sec. toabout 2.5 hours, most preferably from about 5 sec. to about 1 hour. Theinterval between trains can be in the range of from about 1 sec. toabout 1 week, more preferably from about 1 sec. to about 1 day, mostpreferably from about 5 sec. to about 4 hours. Trains can also besupplied on demand if this is determined to be preferable by thephysician or therapist.

The stimulating electrical current can be applied to the vagus nerve anytime after appearance of symptoms associated with persistent impairmentof consciousness, for example within a time period of from about onehour to about three months after appearance of such symptoms.

Finally, the duration of the total therapy can vary depending upon thenature and severity of the impairment, as well as the physicalattributes and condition of the patient. Therapy can vary from about oneday to as long as continued clinical improvement is obtained or desired,e.g., several months or years to the remainder of the patient's life.

As will be recognized by those of ordinary skill in the art, any or allof the foregoing vagus nerve stimulation parameters can be titratedclinically to achieve the desired response in a patient.

The invention being thus described, it will be obvious that the same canbe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the present invention, and allsuch modifications as would be obvious to one skilled in the art areintended to be included within the scope of the following claims.

What is claimed is:
 1. A method of treating a human or animal subjectsuffering from a symptom caused by traumatic brain injury orcharacteristic of traumatic brain injury, comprising:(a) applying to thevagus nerve of a human or animal subject suffering from a symptom causedby traumatic brain injury or characteristic of traumatic brain injury astimulating electrical signal having parameters sufficient to alleviatesaid symptom; (b) monitoring said human or animal subject by clinicaloutcome, a clinical test, a laboratory test, or combinations thereof todetermine if said symptom has been alleviated, or if farther stimulationof said vagus nerve is required, wherein said laboratory test isselected from the group consisting of a brain scan, a PET scan, a SPECTscan, monitoring the level of a neurotransmitter in the brain, andmonitoring the level of a neurotransmitter in spinal fluid; and (c) ifrequired, further stimulating said vagus nerve and monitoring said humanor animal subject as in preceding steps (a) and (b), respectively, untilsaid symptom has been alleviated.
 2. The method of claim 1, wherein saidtraumatic brain injury is associated with a member selected from thegroup consisting of a blow to the head, a penetrating injury to thehead, a fall, a skull fracture, an injury due to sudden acceleration,and an injury due to sudden deceleration.
 3. The method of claim 1,wherein said symptom is selected from the group consisting of impairedlevel of consciousness, impaired cognition, impaired cognitiveprocessing speed, impaired language, impaired motor activity, impairedmemory, impaired motor skills, and impaired sensory skills.
 4. Themethod of claim 1, wherein said electrical signal is produced by astimulus generator implanted within said human or animal subject's body.5. The method of claim 1, wherein said stimulating electrical signal isapplied to said vagus nerve any time after appearance of said symptom.6. The method of claim 1, wherein commencement of application of saidstimulating electrical signal to said vagus nerve is performed within atime period of from about 1 hour to about 3 months after appearance ofsaid symptom.
 7. The method of claim 1, wherein said electrical signalsupplies a current to said vagus nerve in the range of from about 0.1 mAto about 10 mA.
 8. The method of claim 1, wherein said electrical signalsupplies a current to said vagus nerve in the range of from about 0.1 mAto about 4 mA.
 9. The method of claim 1, wherein said electrical signalcomprises a train of pulses, each pulse of which has a pulse width inthe range of from about 50 μsec. to about 1,500 μsec.
 10. The method ofclaim 1, wherein said electrical signal comprises a train of pulses,each pulse of which has a pulse width in the range of from about 400μsec. to about 750 μsec.
 11. The method of claim 1, wherein saidelectrical signal comprises a train of pulses having a frequency in therange of from about 1 Hz to about 75 Hz.
 12. The method of claim 1,wherein said electrical signal comprises a train of pulses having afrequency in the range of from about 10 Hz to about 40 Hz.
 13. Themethod of claim 1, wherein said electrical signal is monophasic,biphasic, or a combination thereof.
 14. The method of claim 1, whereinsaid electrical signal comprises a train of pulses, having a trainduration in the range of from about 1 second to about 4 hours.
 15. Themethod of claim 14, wherein trains are supplied on demand.
 16. Themethod of claim 1, wherein said electrical signal comprises a train ofpulses, having a train duration in the range of from about 5 seconds toabout 1 hour.
 17. The method of claim 1, wherein said electrical signalcomprises trains of pulses, having an interval between trains in therange of from about 1 second to about 1 week.
 18. The method of claim 1,wherein said electrical signal comprises trains of pulses, having aninterval between trains in the range of from about 5 seconds to about 4hours.
 19. The method of claim 1, wherein said clinical test is selectedfrom the group consisting of activities of daily living, memory,cognition, motor skills, development of epilepsy, and FIM score.
 20. Themethod of claim 1, wherein said treating is performed in a time periodin the range of from about one day to as long as continued clinicalimprovement is obtained.
 21. A method of treating a human or animalsubject suffering from a symptom caused by traumatic brain injury orcharacteristic of traumatic brain injury, comprising:(a) applying to thevagus nerve of a human or animal subject suffering from a symptom causedby traumatic brain injury or characteristic of traumatic brain injury astimulating electrical signal having parameters sufficient to alleviatesaid symptom, wherein said symptom is selected from the group consistingof impaired cognition, impaired cognitive processing speed, impairedlanguage, impaired motor activity, impaired memory, impaired motorskills, and impaired sensory skills; (b) monitoring said human or animalsubject to determine if said symptom has been alleviated, or if furtherstimulation of said vagus nerve is required; and (c) if required,further stimulating said vagus nerve and monitoring said human or animalsubject as in preceding steps (a) and (b), respectively, until saidsymptom has been alleviated.
 22. The method of claim 21, wherein saidmonitoring of step (b) is performed via a member selected from the groupconsisting of clinical outcome, a clinical test, a laboratory test, andcombinations thereof.
 23. The method of claim 22, wherein said clinicaltest is selected from the group consisting of activities of dailyliving, memory, cognition, motor skills, development of epilepsy, andFIM score.
 24. The method of claim 22, wherein said laboratory test isselected from the group consisting of a brain scan, a PET scan, a SPECTscan, an EEG, an evoked potential, monitoring the level of aneurotransmitter in the brain, and monitoring the level of aneurotransmitter in spinal fluid.